title: Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug.
abstract: BACKGROUND
  The renoprotective effect of vasopressin V2 receptor antagonist (V2RA) is currently being tested in a clinical trial in early autosomal dominant polycystic kidney disease (ADPKD). If efficacious, this warrants life-long treatment with V2RA, however, with associated side effects as polydipsia and polyuria. We questioned whether we could reduce the side effects without influencing the renoprotective effect by starting the treatment later in the disease or by lowering drug dosage.
  
  
  METHODS
  To investigate this, we administered V2RA OPC-31260 at a high (0.1%) and low (0.05%) dose to a tamoxifen-inducible kidney epithelium-specific Pkd1-deletion mouse model starting treatment at Day 21 (early) or 42 (advanced). After 3 and 6 weeks of treatment, we monitored physiologic and potential renoprotective effects.
  
  
  RESULTS
  Initiation of V2RA treatment at advanced stage of the disease lacked renoprotective effects and had less pronounced physiologic effects than early initiation. After 3 weeks on a high dose, cyst ratio and kidney weight were reduced versus untreated controls (18 versus 25%, P = 0.05, and 0.33 versus 0.45 g, P = 0.03, respectively). After 6 weeks of treatment, however, this did not reach significance anymore, even at a high dose (cyst ratio 24 versus 27%, P = 0.12, and kidney weight 0.55 versus 0.66 g, P = 0.38).
  
  
  CONCLUSIONS
  Our results suggest that intervention with V2RA should be instituted early in ADPKD and that it might be necessary to further increase the dosage of this drug later in the disease to decrease cyst growth.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Meijer
authors.forename: R T
authors.initials: RT
authors.lastname: Gansevoort
authors.forename: P E
authors.initials: PE
authors.lastname: de Jong
authors.forename: A M
authors.initials: AM
authors.lastname: van der Wal
authors.forename: W N
authors.initials: WN
authors.lastname: Leonhard
authors.forename: S R
authors.initials: SR
authors.lastname: de Krey
authors.forename: J
authors.initials: J
authors.lastname: van den Born
authors.forename: G M
authors.initials: GM
authors.lastname: Mulder
authors.forename: H
authors.initials: H
authors.lastname: van Goor
authors.forename: J
authors.initials: J
authors.lastname: Struck
authors.forename: E
authors.initials: E
authors.lastname: de Heer
authors.forename: D J M
authors.initials: DJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000628:therapy; D011493:Protein Kinase C
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; C076251:mozavaptan; C089212:protein kinase D; D011493:Protein Kinase C